Rift Valley fever virus (RVFV) is a prototypical virus of the genus Phlebovirus, family Bunyaviridae, and belongs to the NIAID Category A list pathogens and the CDC list of potential bioterrorism agents. Rift Valley fever is an endemic disease of sub-Saharan Africa that can emerge in explosive mosquito-borne epidemics, decimating herds of sheep and cattle and resulting in enormous economic losses;humans are infected concurrently, and their infection results in hemorrhagic fever, encephalitis, and retinal vasculitis. Many different mosquitoes, including several native to North America, are competent vectors for RVFV epidemic transmission. The introduction of RVFV into North America would likely cause panic in the general population, and the effects on livestock could have a devastating economic impact. Although humoral immunity against the viral envelope proteins elicits protective immunity, there is currently no RVFV vaccine suitable for massive human vaccination programs. MP-12 strain, which was developed by 12 times serial passage of the wild-type RVFV strain ZH548, is markedly attenuated for mice, yet retains immunogenicity. However, the intraperitoneal inoculation of MP-12 into young mice resulted in efficient virus replication in the CNS. The neurovirulence of MP-12 is a concern in developing an immunization method against this virus for the general public;it is possible that MP-12 may invade and replicate efficiently in the CNS of genetically predisposed or temporarily immuno-compromised individuals. The present application proposes development of a novel RVFV vaccine strategy, in which MP-12-based pseudo infectious viruses (PIVs) undergo single-cycle virus replication and production of non- infectious, virus-like particles after immunization. Due to a feature of single-cycle replication, the PIV is highly unlikely to cause systemic infection and invade the CNS of immunized animals and people;yet we expect that a combined effect of single-cycle replication of the PIV and release of immunogenic, virus-like particles will induce a strong immune response to RVFV proteins. We will test the immunogenicity, neuroinvasiveness and neurovirulence of the PIV and examine whether PIV immunization confers protection to animals immunized following wt RVFV challenge in mouse models. The proposed studies will be valuable for generation of a highly immunogenic RVFV vaccine candidate with increased safety and suitable for future product development and human testing.

Public Health Relevance

Rift Valley fever virus causes an endemic disease for livestock and humans in sub-Saharan Africa, and there is serious concern that this virus could be introduced into North America. There is currently no Rift Valley fever virus vaccine suitable for massive human vaccination programs. This research program seeks to develop a novel Rift Valley fever virus vaccine.